Nicotinic acid riboside or nicotinamide riboside compositions, reduced derivatives thereof, and the use thereof to enhance skin permeation in treating skin conditions

Patent metadata

Field	Value
Publication number	US-10280190-B2
Application number	US-201615072121-A
Country	US
Kind code	B2
Filing date	Mar 16, 2016
Priority date	Mar 16, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

Derivatives of nicotinic acid riboside (NAR), nicotinamide riboside (NR), and reduced NAR and NR, including 1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid (4a), and compositions containing the same and/or reduced derivative forms of nicotinamide riboside including 1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-nicotinamide (2), are provided for use in the care of treatment of skin and skin conditions. In some embodiments, the invention relates to pharmaceutical compositions and cosmetic compositions containing one or more NR, NAR, NRH, or NARH derivatives, or prodrugs or salts thereof. In further embodiments, the invention relates to methods of using one or more NR, NAR, NRH, or NARH derivatives, or prodrugs, solvates, or salts thereof, to promote the increase of intracellular levels of nicotinamide adenine dinucleotide (NAD+) in cells and tissues for improving cell and tissue survival and overall cell and tissue health.

First claim

We claim:

1. A compound of formula (II-Hc), or a salt or solvate thereof:

wherein R 1 is selected from hydrogen and (C 1 -C 4 )alkyl;
wherein R 6 is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle;
R′ is selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 4 )alkyl, and heterocycle(C 1 -C 4 )alkyl; and
R 7 and R 8 are independently selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C 1 -C 4 )alkyl, and substituted or unsubstituted heterocycle(C 1 -C 4 )alkyl;
provided that R 1 is not ethyl;
provided that when R 1 , R 7 , and R 8 are simultaneously hydrogen, then R 6 is not C(O)-aryl;
provided that R 1 , R 6 , R 7 , and R 8 are not all simultaneously hydrogen; and
provided that when R 1 is (C 1 -C 4 )alkyl, then R 6 , R 7 , and R 8 are not all simultaneously C(O)R′, wherein R′ is (C 1 -C 8 )alkyl.

2. A compound of claim 1 which is 1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid, or a salt or solvate thereof.

3. A cytoprotective method for treating skin damage in an individual comprising administering in need of such treatment a therapeutically effective amount of at least one compound of formula (I-Ha), or a salt or solvate thereof:

wherein R 6 is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle;
R′ is selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 4 )alkyl, and heterocycle(C 1 -C 4 )alkyl;
R 7 and R 8 are independently selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C 1 -C 4 )alkyl, and substituted or unsubstituted heterocycle(C 1 -C 4 )alkyl;
provided that in formula (I-Ha), when R 6 is —C(O)R′ or —C(O)OR′, and R′ is unsubstituted (C 1 -C 8 )alkyl or unsubstituted (C 3 -C 8 )cycloalkyl or unsubstituted aryl, then R 7 and R 8 are not simultaneously hydrogen or —C(O)R′ or —C(O)OR′; or
at least one compound of formula (II-Hc), or a salt or solvate thereof:

wherein R 6 , R 7 , and R 8 are as defined above for the compounds of formula (I-Ha) and wherein R 1 is selected from hydrogen and (C 1 -C 4 )alkyl.

4. The cytoprotective method of claim 3 , wherein the individual is a human.

5. The cytoprotective method of claim 3 , wherein the at least one compound, or a salt or solvate thereof, is provided in a composition comprising a pharmaceutically acceptable carrier.

6. The cytoprotective method of claim 3 , wherein the method of administration is selected from the group consisting of oral, topical, sublingual, buccal, ocular, pulmonary, rectal, parenteral, nasal, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, intravaginal, intravesical, intradermal, transdermal, and subcutaneous.

7. The cytoprotective method of claim 3 , wherein skin damage is selected from the group consisting of oxidative damage, aging, superficial wrinkles, a coarse deep wrinkle, enlarged pores, age spots, photodamage, scaliness, flakiness, dryness, sagging in skin, puffiness in skin around an eye, puffiness in skin around a jowl, reduction of skin elasticity, reduction of skin firmness, reduction of skin tightness, reduction of barrier function, reduction of skin recoil from deformation, discoloration, blotching, sallowness, hyperpigmentation, keratosis, hyperkeratinization, elastosis, collagen breakdown, and combinations thereof.

8. The cytoprotective method of claim 3 , wherein the at least one compound, or a salt or solvate thereof, is selected from the group consisting of: reduced nicotinic acid riboside (NARH), reduced nicotinamide riboside (NRH), and 1-(2′,3′,5′)-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid (NARH-TA).

9. The cytoprotective method of claim 3 , wherein the at least one compound is a salt of 1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid (NARH-TA), the counterion of which is selected from the group consisting of sodium, potassium, lithium, magnesium, and calcium.

10. The cytoprotective method of claim 3 , wherein the therapeutically effective amount of the at least one compound, or a salt or solvate thereof, for a total dose is in a range of about 0.1% by weight to about 50% by weight based on the total weight of the composition.

11. The cytoprotective method of claim 3 , wherein the therapeutically effective amount of the at least one compound, or a salt or solvate thereof, for a total dose is in a range of about 0.1% by weight to about 10% by weight based on the total weight of the composition.

12. The cytoprotective method of claim 9 , wherein skin cell viability is at least about 75%.

13. The cytoprotective method of claim 9 , where skin cell viability is at least about 80%.

14. The cytoprotective method of claim 9 , where skin cell viability is at least about 90%.

15. A cytoprotective method of treating skin damage in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (Ia), or a salt or solvate thereof:

wherein R 6 is selected from the group consisting of, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle;
R′ is selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 4 )alkyl, and heterocycle(C 1 -C 4 )alkyl; and
R 7 and R 8 are independently selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C 1 -C 4 )alkyl, and substituted or unsubstituted heterocycle(C 1 -C 4 )alkyl;
provided that in formula (Ia), R 6 , R 7 , and R 8 are not all sim

Assignees

• Chromadex Inc
• Univ Belfast

Inventors

• Dellinger Ryan
• Migaud Marie Eugenie
• Redpath Philip
• Rhonemus Troy
• Cunningham Richard

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61Q19/00

  Preparations for care of the skin · CPC title

• A61K8/675

  Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde (tocopheryl nicotinate A61K8/678) · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• C07H19/048 Primary

  Pyridine radicals · CPC title